[TKIS-P] Takao International Session（II-TKIS-P）
e-Poster

[II-TKIS-P-2] Sex-specific cardiotoxicity modeled by twin-derived human iPS cells

^○Akihito Ota¹, Masashi Wakabayashi¹, Satoshi Shimizu¹, Kazuho Sakamoto^1,2, Masami Kodama¹, Yoichi Sunagawa³, Yasunari Kanda⁴, Tatsuya Morimoto^3,5, Junko Kurokawa¹ (1.Dept. Bio-inform. Pharmacol., University of Shizuoka, Shizuoka, Japan, 2.Dept. Pharm. Sci., International Univ. of Health and Welfare, Tochigi, Japan, 3.Div. Mol. Med., University of Shizuoka, Shizuoka, Japan, 4.Div. Pharmacol., NIHS, Kanagawa, Japan, 5.Dept. Pharmacol., Toho university, Tokyo, Japan)

キーワード：

iPS cells、sex-differences、cardiac repolarization

Sex differences impact cardiovascular disease and drug-induced cardiotoxicity susceptibility. Mechanisms remain elusive without human models incorporating both sex hormones and sex chromosomes. We aimed to elucidate sex-specific cardiotoxicity mechanisms using human induced pluripotent stem cells (hiPSCs) derived from sex-discordant dizygotic twins to provide a controlled genetic background. T cells from twin donors were reprogrammed via Sendai virus. Three hiPSC lines per donor were differentiated into cardiomyocytes (hiPSC-CMs). Transcriptomic profiles were compared via RNA-sequencing. To assess pharmacological responses, female hiPSC-CMs were exposed to the hERG blocker E-4031 under simulated late follicular phase hormone conditions. Contractility was evaluated using motion vector waveform analysis. RNA-sequencing revealed distinct sex-dependent transcriptomic profiles in iPS cells. E-4031 exposure caused a concentration-dependent prolongation of contraction-relaxation duration (CRD). Crucially, the addition of female hormones lowered the threshold concentration for CRD prolongation, mimicking the increased clinical susceptibility to drug-induced arrhythmias observed in females. This twin-derived hiPSC-CM model provides a robust platform for investigating sex-related cardiac biology. Integrating hormone-specific conditions enhances the predictive accuracy of pharmacological assays, elucidating human-specific cardiotoxicity mechanisms.